Alzheimer's Disease (AD) is the most common neurodegenerative disorder and most common cause of dementia in older populations. AD is a progressive neurological disorder characterized by cognitive and non- cognitive symptoms that result from brain atrophy. The hippocampus is critical for learning and memory and neurodegeneration in this brain region is thought to be involved in the cognitive and memory deficits in AD. Alcohol (EtOH) is the most commonly abused drug worldwide, is a leading risk factor for global disease burden, and alcohol use disorders (AUDs) are strongly associated with a high risk of dementia. Though the relationship between EtOH use and risk of AD is complex, an increased risk of AD from EtOH consumption is observed in those who abuse or heavily consume EtOH. Heavy EtOH consumption is associated with more cognitive decline in AD patients suggesting that EtOH may hasten the progression of AD. In AD mutant mice, chronic EtOH treatment promoted an increase in hippocampal amyloid ? (A?) plaques, a neuropathological hallmark of AD linked to neuronal death, and deficits in spatial memory and learning. The parent grant for this supplement is based upon our finding that regulator of G protein signaling 6 (RGS6) promotes EtOH seeking and reward behaviors in mice and a subsequent GWAS identifying RGS6 as a novel AUD gene in humans. The role of RGS6 in EtOH seeking, reward, dependence and withdrawal appears to be due to its critical modulation of dopamine (DA) release from ventral tegmental area (VTA) neurons to the nucleus accumbens (NAc), the major neuronal circuit involved in EtOH and drug seeking and addiction. This proposal is based upon our recent evidence that RGS6 functions as a critical mediator of VTA DA neuronal silencing during chronic EtOH treatment of mice. The relevance of these findings to AD is considerable given findings that AD mutant mice undergo loss of VTA DA neurons that drive hippocampal dysfunction as well as evidence that EtOH exacerbates hippocampal neuropathology and cognitive loss in AD mice. Here we propose to test the central hypothesis that RGS6 promotes EtOH-induced VTA DA neuron dysfunction that contributes to hippocampal deficits in AD. Aim 1 will determine the role of RGS6 in VTA DA neurons on chronic EtOH-induced neuropathological features and cognitive function in an APP model of AD. We will determine the role of RGS6-mediated VTA DA neuronal silencing on spatial learning and memory and hippocampal neurodegeneration and A? pathology in control and AD mice following chronic EtOH treatment. These studies are highly significant as they will illuminate an entirely novel modulatory mechanism present in the mesolimbic circuit implicated not only in EtOH behavioral reward/addiction but also in AD associated hippocampal dysfunction. RGS6 is an AUD gene in humans and our studies may lead to new understanding of why AUD is associated with a high risk of dementias and increased risk of AD.